Central dogma of molecular biology

The central dogma of molecular biology is an explana- 1 Biological sequence information

tion of the ow of genetic information within a biological
system. It was rst stated by Francis Crick in 1958[1]
and re-stated in a Nature paper published in 1970:[2]
Main article: Primary structure
The biopolymers that comprise DNA, RNA and
(poly)peptides are linear polymers (i.e.: each monomer is
connected to at most two other monomers). The sequence
of their monomers eectively encodes information. The
transfers of information described by the central dogma
ideally are faithful, deterministic transfers, wherein one
biopolymers sequence is used as a template for the con-
struction of another biopolymer with a sequence that is
entirely dependent on the original biopolymers sequence.

2 General transfers of biological

sequential information

Central Dogma of Molecular Biology : Eukaryotic Model

DNA
Information ow in biological systems
ATG
Intron Exon
Promoter
Region

TATA
UGA
Stop CodonsUAA
Transcription and mRNA processing UAG
5 Un-Translated Region

The central dogma has also been described as DNA mRNA

5 Cap
AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA
3 Poly A tail

makes RNA and RNA makes protein,[3] originally Translation

Protein
termed the sequence hypothesis and made as a positive
Methionine

statement by Crick. However, this simplication does not Post-Translational Modication

make it clear that the central dogma as stated by Crick PO4

does not preclude the reverse ow of information from

PO4
S S
Active Protein

RNA to DNA, only ruling out the ow from protein to

RNA or DNA. Cricks use of the word dogma was un-
conventional, and has been controversial.
The dogma is a framework for understanding the transfer
of sequence information between information-carrying
biopolymers, in the most common or general case, in liv-
ing organisms. There are 3 major classes of such biopoly-
mers: DNA and RNA (both nucleic acids), and protein. 2.1 DNA replications
There are 33 = 9 conceivable direct transfers of infor-
mation that can occur between these. The dogma classes Main article: DNA replication
these into 3 groups of 3: 3 general transfers (believed to
occur normally in most cells), 3 special transfers (known
to occur, but only under specic conditions in case of In the sense that DNA replication must occur if genetic
some viruses or in a laboratory), and 3 unknown trans- material is to be provided for the progeny of any cell,
fers (believed never to occur). The general transfers de- whether somatic or reproductive, the copying from DNA
scribe the normal ow of biological information: DNA to DNA arguably is the fundamental step in the central
can be copied to DNA (DNA replication), DNA informa- dogma. A complex group of proteins called the replisome
tion can be copied into mRNA (transcription), and pro- performs the replication of the information from the par-
teins can be synthesized using the information in mRNA ent strand to the complementary daughter strand.
as a template (translation).[2] The replisome comprises:

1
2 3 SPECIAL TRANSFERS OF BIOLOGICAL SEQUENTIAL INFORMATION

a helicase that unwinds the superhelix as well as the the primary transcript is pre-mRNA. Pre-mRNA must be
double-stranded DNA helix to create a replication processed for translation to proceed. Processing includes
fork the addition of a 5' cap and a poly-A tail to the pre-mRNA
chain, followed by splicing. Alternative splicing occurs
SSB protein that binds open the double-stranded when appropriate, increasing the diversity of the proteins
DNA to prevent it from reassociating that any single mRNA can produce. The product of the
RNA primase that adds a complementary RNA entire transcription process (that began with the produc-
primer to each template strand as a starting point tion of the pre-mRNA chain) is a mature mRNA chain.
for replication
DNA polymerase III that reads the existing template 2.3 Translation
chain from its 3' end to its 5' end and adds new com-
plementary nucleotides from the 5' end to the 3' end Main article: Translation (genetics)
of the daughter chain
DNA polymerase I that removes the RNA primers The mature mRNA nds its way to a ribosome, where
and replaces them with DNA. it gets translated. In prokaryotic cells, which have
no nuclear compartment, the processes of transcrip-
DNA ligase that joins the two Okazaki fragments
tion and translation may be linked together without
with phosphodiester bonds to produce a continuous
clear separation. In eukaryotic cells, the site of tran-
chain.
scription (the cell nucleus) is usually separated from
the site of translation (the cytoplasm), so the mRNA
This process typically takes place during S phase of the must be transported out of the nucleus into the cyto-
cell cycle. plasm, where it can be bound by ribosomes. The ri-
bosome reads the mRNA triplet codons, usually begin-
ning with an AUG (adenineuracilguanine), or initia-
2.2 Transcription tor methionine codon downstream of the ribosome bind-
ing site. Complexes of initiation factors and elongation
factors bring aminoacylated transfer RNAs (tRNAs) into
the ribosome-mRNA complex, matching the codon in
the mRNA to the anti-codon on the tRNA. Each tRNA
bears the appropriate amino acid residue to add to the
polypeptide chain being synthesised. As the amino acids
get linked into the growing peptide chain, the chain be-
gins folding into the correct conformation. Translation
ends with a stop codon which may be a UAA, UGA, or
UAG triplet.
The mRNA does not contain all the information for spec-
ifying the nature of the mature protein. The nascent
polypeptide chain released from the ribosome commonly
requires additional processing before the nal product
emerges. For one thing, the correct folding process is
complex and vitally important. For most proteins it re-
quires other chaperone proteins to control the form of
the product. Some proteins then excise internal segments
from their own peptide chains, splicing the free ends that
border the gap; in such processes the inside discarded
sections are called inteins. Other proteins must be split
into multiple sections without splicing. Some polypep-
tide chains need to be cross-linked, and others must be
attached to cofactors such as haem (heme) before they
Main article: Transcription (genetics) become functional.

Transcription is the process by which the information

contained in a section of DNA is replicated in the 3 Special transfers of biological se-
form of a newly assembled piece of messenger RNA
(mRNA). Enzymes facilitating the process include RNA quential information
polymerase and transcription factors. In eukaryotic cells
4.1 Posttranslational modication
3.1 Reverse transcription
Unusual ow of information highlighted in green
Main article: Reverse transcription
Reverse transcription is the transfer of information from
RNA to DNA (the reverse of normal transcription). This
is known to occur in the case of retroviruses, such as HIV,
as well as in eukaryotes, in the case of retrotransposons
and telomere synthesis. It is the process by which genetic
information from RNA gets transcribed into new DNA.
3.2 RNA replication
RNA replication is the copying of one RNA to another.
Many viruses replicate this way. The enzymes that copy
RNA to new RNA, called RNA-dependent RNA poly-
merases, are also found in many eukaryotes where they
are involved in RNA silencing.[4]
RNA editing, in which an RNA sequence is altered by a
complex of proteins and a guide RNA, could also be
seen as an RNA-to-RNA transfer.
3.3 Direct translation from DNA to pro-
tein
Direct translation from DNA to protein has been demon-
strated in a cell-free system (i.e. in a test tube), using
extracts from E. coli that contained ribosomes, but not in-
tact cells. These cell fragments could synthesize proteins
from single-stranded DNA templates isolated from other
organisms (e,g., mouse or toad), and neomycin was found
to enhance this eect. However, it was unclear whether
this mechanism of translation corresponded specically
to the genetic code.[5][6]
4 Transfers of information not ex-
plicitly covered in the theory
3
4.1 Posttranslational modication
Main article: Posttranslational modication
After protein amino acid sequences have been translated
from nucleic acid chains, they can be edited by appropri-
ate enzymes. Although this is a form of protein aect-
ing protein sequence, not explicitly covered by the central
dogma, there are not many clear examples where the as-
sociated concepts of the two elds have much to do with
each other.
4.2 Inteins
Main article: Intein
An intein is a parasitic segment of a protein that is able
to excise itself from the chain of amino acids as they
emerge from the ribosome and rejoin the remaining por-
tions with a peptide bond in such a manner that the main
protein backbone does not fall apart. This is a case of a
protein changing its own primary sequence from the se-
quence originally encoded by the DNA of a gene. Addi-
tionally, most inteins contain a homing endonuclease or
HEG domain which is capable of nding a copy of the
parent gene that does not include the intein nucleotide
sequence. On contact with the intein-free copy, the HEG
domain initiates the DNA double-stranded break repair
mechanism. This process causes the intein sequence to
be copied from the original source gene to the intein-free
gene. This is an example of protein directly editing DNA
sequence, as well as increasing the sequences heritable
propagation.
4.3 Methylation
Main article: Epigenetics
Variation in methylation states of DNA can alter gene ex-
pression levels signicantly. Methylation variation usu-
ally occurs through the action of DNA methylases. When
the change is heritable, it is considered epigenetic. When
the change in information status is not heritable, it would
be a somatic epitype. The eective information content
has been changed by means of the actions of a protein or
proteins on DNA, but the primary DNA sequence is not
altered.
4.4 Prions
Main article: Prion
Prions are proteins of particular amino acid sequences
in particular conformations. They propagate themselves
4 7
in host cells by making conformational changes in other
molecules of protein with the same amino acid sequence,
but with a dierent conformation that is functionally im-
portant or detrimental to the organism. Once the protein Similarly, Horace Freeland Judson records in The Eighth
has been transconformed to the prion folding it changes Day of Creation:[12]
function. In turn it can convey information into new cells
and recongure more functional molecules of that se-
quence into the alternate prion form. In some types of
prion in fungi this change is continuous and direct; the
information ow is Protein Protein.
Some scientists such as Alain E. Bussard and Eugene
Koonin have argued that prion-mediated inheritance vio-
lates the central dogma of molecular biology.[7][8] How-
ever, Rosalind Ridley in Molecular Pathology of the Pri-
ons (2001) has written that The prion hypothesis is not
heretical to the central dogma of molecular biology
that the information necessary to manufacture proteins 6 See also
is encoded in the nucleotide sequence of nucleic acid
because it does not claim that proteins replicate. Rather,
it claims that there is a source of information within pro-
tein molecules that contributes to their biological func-
tion, and that this information can be passed on to other
molecules.[9]
4.5 Natural genetic engineering
James A. Shapiro argues that a superset of these examples
should be classied as natural genetic engineering and are
sucient to falsify the central dogma. While Shapiro has
received a respectful hearing for his view, his critics have
not been convinced that his reading of the central dogma
is in line with what Crick intended.[10] [11]
5 Use of the term dogma
In his autobiography, What Mad Pursuit, Crick wrote
about his choice of the word dogma and some of the prob-
lems it caused him:
I called this idea the central dogma, for
two reasons, I suspect. I had already used
the obvious word hypothesis in the sequence
hypothesis, and in addition I wanted to sug-
gest that this new assumption was more cen-
tral and more powerful. ... As it turned out,
the use of the word dogma caused almost more
trouble than it was worth. Many years later
Jacques Monod pointed out to me that I did
not appear to understand the correct use of the
word dogma, which is a belief that cannot be
doubted. I did apprehend this in a vague sort
of way but since I thought that all religious be-
liefs were without foundation, I used the word
the way I myself thought about it, not as most
of the world does, and simply applied it to a
REFERENCES
grand hypothesis that, however plausible, had
little direct experimental support.
My mind was, that a dogma was an idea
for which there was no reasonable evidence.
You see?!" And Crick gave a roar of delight.
I just didn't know what dogma meant. And
I could just as well have called it the 'Central
Hypothesis,' or you know. Which is what I
meant to say. Dogma was just a catch phrase.
Alternative splicing
Genetic code
Riboswitch
Weismann barrier
7 References
[1] Crick, F.H.C. (1956): On Protein Synthesis. Symp. Soc.
Exp. Biol. XII, 139-163. (pdf, early draft of original
article)
[2] Crick, F (August 1970). Central dogma of molec-
ular biology. (PDF). Nature. 227 (5258): 5613.
Bibcode:1970Natur.227..561C. doi:10.1038/227561a0.
PMID 4913914.
[3] Leavitt, Sarah A. (June 2010). Deciphering the Genetic
Code: Marshall Nirenberg. Oce of NIH History.
[4] Ahlquist P (May 2002). RNA-dependent RNA
polymerases, viruses, and RNA silencing. Science.
296 (5571): 12703. Bibcode:2002Sci...296.1270A.
doi:10.1126/science.1069132. PMID 12016304.
[5] B. J. McCarthy; J. J. Holland (September 15, 1965).
Denatured DNA as a Direct Template for in vitro
Protein Synthesis. Proceedings of the National
Academy of Sciences of the United States of America.
54 (3): 880886. Bibcode:1965PNAS...54..880M.
doi:10.1073/pnas.54.3.880. PMC 219759 . PMID
4955657.
[6] .T. Uzawa; A. Yamagishi; T. Oshima (2002-04-09).
Polypeptide Synthesis Directed by DNA as a Messen-
ger in Cell-Free Polypeptide Synthesis by Extreme Ther-
mophiles, Thermus thermophilus HB27 and Sulfolobus
tokodaii Strain 7. The Journal of Biochemistry. 131 (6):
849853. doi:10.1093/oxfordjournals.jbchem.a003174.
PMID 12038981.
 5

[7] Bussard Alain E (2005). A scientic revolution? The 9 External links

prion anomaly may challenge the central dogma of
molecular biology. EMBO Rep. 6 (8): 691694. The Elaboration of the Central Dogma Scitable:
doi:10.1038/sj.embor.7400497. PMC 1369155 . PMID By Nature education
16065057.
Animation of Central Dogma from RIKEN - Na-
[8] Koonin, Eugene. (2012). Does the Central Dogma Still tureDocumentaries.org
Stand? Biology Direct 7: 27.
Discussion on challenges to the Central Dogma of
[9] Ridley, Rosalind. (2001). What Would Thomas Henry Molecular Biology
Huxley Have Made of Prion Diseases?. In Harry F. Baker.
Molecular Pathology of the Prions (Methods in Molecular Explanation of the central dogma using a musical
Medicine). Humana Press. pp. 1-16. ISBN 0-89603-924- analogy
2
Francis Harry Compton Crick (19162004)" by A.
[10] Wilkins, Adam S. (January 2012). "(Review) Evolution: Andrei at the Embryo Project Encyclopedia
A View from the 21st Century. Genome Biology and
Evolution. 4: 423426. doi:10.1093/gbe/evs008.

[11] Moran, Laurence A (MayJune 2011). "(Review) Evo-

lution: A View from the 21st Century. Reports of the
National Center for Science Education. 32.3 (9): 14.

[12] Horace Freeland Judson (1996). Chapter 6: My mind

was, that a dogma was an idea for which there was no
reasonable evidence. You see?!". The Eighth Day of Cre-
ation: Makers of the Revolution in Biology (25th anniver-
sary edition). Cold Spring Harbor, NY: Cold Spring Har-
bor Laboratory Press. ISBN 0-87969-477-7.

8 Further reading
Bussard Alain E (2005). A scientic revolution?
The prion anomaly may challenge the central dogma
of molecular biology. EMBO Rep. 6 (8): 691694.
doi:10.1038/sj.embor.7400497. PMC 1369155 .
PMID 16065057.

Baker, Harry F. (2001). Molecular Pathology of the

Prions (Methods in Molecular Medicine). Humana
Press. ISBN 0-89603-924-2

Koonin Eugene (2012). Does the Central

Dogma Still Stand?". Biology Direct. 7: 27.
doi:10.1186/1745-6150-7-27.

Li J. J; Biggin M. D. (2015). Gene ex-

pression. Statistics requantitates the central
dogma. Science. 347 (6226): 10661067.
doi:10.1126/science.aaa8332.

Piras V, Tomita M, Selvarajoo K (2012). Is cen-

tral dogma a global property of cellular informa-
tion ow?". Frontiers in Physiology. 3: 439.
doi:10.3389/fphys.2012.00439.

Robinson Victoria L (2009). Rethinking the Cen-

tral Dogma: noncoding RNAs are biologically rel-
evant. Urologic Oncology. 27 (3): 304306.
doi:10.1016/j.urolonc.2008.11.004.
6 10 TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES

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